Abstract 3408: Cancer-specific anti-HER2 monoclonal antibodies demonstrate antitumor activities in human breast cancer xenograft models

Abstract Monoclonal antibody (mAb) therapy represents cutting-edge strategies for cancer treatment. In contrast, safety concerns persist due to the potential targeting of normal cells that express reactive antigens. Developing cancer-specific mAbs (CasMabs) that bind to cancer-specific antigens and exhibit antitumor activity in vivo is critical for reducing the risk of adverse effects. Herein, we selected mAbs targeting human epidermal growth factor receptor 2 (HER2) and successfully established an anti-HER2 CasMab (clone H2CasMab-2; mouse IgG1, kappa). We investigated both the in vitro and in vivo antitumor efficacy using three types of H2CasMab-2: the mouse IgG2a type of H2CasMab-2 (H2CasMab-2-mG2a), the mouse-human chimeric H2CasMab-2 (H2CasMab-2-hG1), and the humanized H2CasMab-2 (humH2CasMab-2). H2CasMab-2 showed lower reactivity to HER2-overexpressed Chinese hamster ovary-K1 (CHO/HER2) and breast cancer cell lines (BT-474 and SK-BR-3) than trastuzumab in flow cytometry. Every format of H2CasMab-2 also showed lower antibody-dependent cellular cytotoxicity (ADCC) against CHO/HER2 and the breast cancer cell lines than trastuzumab. In contrast, every format of H2CasMab-2 exhibited significantly higher complement-dependent cellular cytotoxicity (CDC) in CHO/HER2 and breast cancer cells than trastuzumab. Furthermore, every format of H2CasMab-2 demonstrated compatible in vivo antitumor effects against breast cancer xenografts with trastuzumab. These findings highlight the distinct roles of ADCC and CDC in the antitumor effects of H2CasMab-2 and trastuzumab and suggest a potential direction for the clinical development of H2CasMab-2 for HER2-positive tumors. Citation Format: Yukinari Kato, Tomokazu Ohishi, Tomohiro Tanaka, Hiroyuki Suzuki, Mika K. Kaneko. Cancer-specific anti-HER2 monoclonal antibodies demonstrate antitumor activities in human breast cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3408.